Kidney disease is increasing at epidemic rates in the US. One clinical sign of kidney disease is protein in the urine (proteinuria). This is typically due to a leak in the normal filtration barrier, and in part is due to injury to a cell called the podocyte. Podocytes are specialized cells that function to limit proteinuria. However, in many diseases including diabetes, podocytes are injured to the point of death, referred to as apoptosis. Moreover, as podocytes die, the remaining podocytes are unable to proliferate and replenish those lost, resulting in a decrease in podocyte number. This further reduces the barrier function of these cells and ultimately leads to kidney failure. The purpose of this grant is to define novel mechanisms underlying podocyte death. Our group has focused in molecules called cell cycle proteins, which reside in the nucleus of the cell. In this grant, we will test the hypothesis that newly discovered cell cycle proteins called cyclin I and cdk5 form a complex which functions to protect podocytes from death in disease. We also believe another partner called p21 adds to this protective function. We will explore possibilities using podocytes in a cell culture system, and also in mice that have been genetically altered to be born without cyclin I, cdk5 and p21. The overall goal is to delineate new paradigms in the regulation of podocyte survival and death, so that ultimately new strategies can be developed to prevent podocyte loss, enhance kidney survival, and reduce kidney disease.